Recurrence risk of congenital malformations in infants exposed to antiepileptic drugs in utero.

PURPOSE: Use of antiepileptic drugs in pregnancy is associated with congenital malformations and developmental delay. Previous studies have suggested that women who have had one child with a congenital malformation are at increased risk of having other children with malformations. We sought to confirm the magnitude of risk in a large cohort drawn from the United Kingdom Epilepsy and Pregnancy Register. METHODS: The United Kingdom Epilepsy and Pregnancy Register is a prospective, observational registration and follow-up study set up to determine the relative safety of antiepileptic drugs in pregnancy. We have extracted data for those women who prospectively registered more than one pregnancy and calculated the recurrence risks for fetal malformations. KEY FINDINGS: Outcome data were available for 1,534 pregnancies born to 719 mothers. For women whose first child had a congenital malformation there was a 16.8% risk of having another child with a congenital malformation, compared with 9.8% for women whose first child did not have a malformation (relative risk 1.73, 95% confidence interval [CI] 1.01-2.96). The risk for recurrence was 50% for women who had had two previous children with a congenital malformation. There was a trend toward a higher risk for recurrent malformations in pregnancies exposed to valproate (21.9%, relative risk 1.47, 95% CI 0.68-3.20) and topiramate (50%, relative risk 4.50, 95% CI 0.97-20.82), but not for other drugs such as carbamazepine and lamotrigine. Recurrence risks were also higher for pregnancies exposed to polytherapy regimens and for those where the dose of antiepileptic drug treatment had been increased after the first pregnancy. SIGNIFICANCE: Women who have had a child with a malformation are at increased risk of having other children with malformations. This is in keeping with previous reports that have suggested that genetic influences may be one of the factors determining the teratogenic risk of antiepileptic drugs.

Pregnancy registries: differences, similarities, and possible harmonization.

Epilepsy and pregnancy registries have been operational for more than 10 years, have accrued considerable experience, and collected an impressive amount of data. As findings have been published, it has become important to understand how observations from the different registries are comparable, especially since their methodologies differ somewhat. In September 2008, representatives of the UK Epilepsy and Pregnancy Register, the North American AED Pregnancy Registry (NAAPR), and the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) met for a workshop. Their objectives were to exchange information on their methodologies and to discuss areas where harmonization might be possible. This report summarizes these discussions.

Psychological processes and histories associated with nonepileptic versus epileptic seizure presentations.

Nonepileptic seizures (NES) provide a clinical challenge as the mechanisms involved remain uncertain. The present study compares 27 participants with confirmed NES presentations with 39 individuals with epileptic seizure (ES) presentations only, on indices of psychopathology, trauma history, dissociative propensity, and attachment style. Psychopathology and dissociation were found to be significantly elevated in the NES group compared with the ES group. No differences were found between groups in terms of trauma history and attachment style. However, trauma history did correlate significantly with psychopathology in the NES group but not in the ES group. Finally, whereas the relationship between psychological variables and seizure frequency was weak within the ES group, trauma history, a fearful attachment dimension, psychopathology, and dissociation predicted seizure frequency in the NES group. Implications for understanding and interventions with NES presentations are discussed.

The preconception care experiences of women with epilepsy on sodium valproate.

PURPOSE: To understand the preconception experiences of women with epilepsy who have been taking the teratogenic drug valproate. METHODS: Seven women were recruited, three from a preconception clinic and four from an antenatal clinic in a region of the UK. All had taken valproate preconceptionally. Three preconception clinic encounters were observed and audio-recorded. Interviews with all women were analysed using Interpretative Phenomenological Analysis (IPA). RESULTS: Women experienced a "trajectory of balance". Women moved from "maintaining balance" by using valproate to control seizures, to a "shattering of harmony" at the prospect of changing medication and as a result of the physical and mental effects of changing medication, to "restoring balance" which could involve "a new self" due to dramatic changes. Women balanced their health needs with those of their baby, and took responsibility for medication decision-making. They found it difficult to see "who is looking after me" in the healthcare system, either to access preconception care, or to support them through the stress of changing medication. Their journey ended with coming to terms with a variety of experiences: choosing not to have a baby due to unsuccessful change from valproate, recognising that a child from a previous pregnancy had been harmed by valproate or that the current pregnancy might be at risk, or successful medication change in preparation for pregnancy. CONCLUSION: A clear and adequately funded preconception care pathway is needed from epilepsy diagnosis, including support for stress. Understanding what influences maternalisation may help understand uptake of preconception care.

Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers.

OBJECTIVES: Levetiracetam is a broad-spectrum antiepileptic drug (AED) which is currently licensed in the United States and the United Kingdom and Ireland for use as adjunctive treatment of focal-onset seizures and myoclonic seizures or generalized tonic-clonic seizures, occurring as part of generalized epilepsy syndromes. In the United Kingdom and Ireland, it is also licensed as monotherapy treatment for focal-onset seizures. Previous small studies have suggested a low risk for major congenital malformations (MCM) with levetiracetam use in pregnancy. METHODS: The UK and Ireland Epilepsy and Pregnancy Registers are prospective, observational registration and follow-up studies that were set up to determine the relative safety of all AEDs taken in pregnancy. Here we report our combined results for first-trimester exposures to levetiracetam from October 2000 to August 2011. RESULTS: Outcome data were available for 671 pregnancies. Of these, 304 had been exposed to levetiracetam in monotherapy, and 367 had been exposed to levetiracetam in combination with at least one other AED. There were 2 MCM in the monotherapy group (0.70%; 95% confidence interval [CI] 0.19%-2.51%) and 19 in the polytherapy group 5.56% (3.54%­8.56%) [corrected]. The MCM rate in the polytherapy group varied by AED regimen, with lower rates when levetiracetam was given with lamotrigine (1.77%; 95% CI 0.49%-6.22%) than when given with valproate (6.90%; 95% CI 1.91%-21.96%) or carbamazepine (9.38%; 95% CI 4.37%-18.98%). CONCLUSION: This study, in a meaningful number of exposed pregnancies, confirms a low risk for MCM with levetiracetam monotherapy use in pregnancy. MCM risk is higher when levetiracetam is taken as part of a polytherapy regimen, although further work is required to determine the risks of particular combinations. With respect to MCM, levetiracetam taken in monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age.

Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine.

OBJECTIVE: To establish the relative risks of in utero exposure to lamotrigine (LTG), sodium valproate (NaV) and carbamazepine (CBZ) monotherapy for neurodevelopment. DESIGN: Observational cohort study. PATIENTS AND METHODS: The study group consisted of children in Northern Ireland aged 9-60 months born to mothers who had enrolled with the UK Epilepsy and Pregnancy Register. The control group consisted of children identified from the Child Health System database across Northern Ireland. Data were gathered on covariates recognised as influencing child development. MAIN OUTCOME MEASURES: Neurodevelopment assessed using either the Bayley Scales of Infant Development or the Griffiths Mental Development Scales. RESULTS: 210 children underwent assessment by a single researcher blinded to antiepileptic drug exposure. 23 (39.6%) children exposed in utero to NaV, 10 (20.4%) exposed to CBZ and one (2.9%) exposed to LTG had evidence of mild or significant developmental delay, compared to two (4.5%) children in the control group. Multivariable analysis demonstrated that in utero exposure to NaV (OR 26.1, 95% CI 4.9 to 139; p<0.001) and to CBZ (OR 7.7, 95% CI 1.4 to 43.1; p<0.01) but not to LTG had a significant detrimental effect on neurodevelopment. CONCLUSION: In utero exposure to LTG did not have the detrimental effect on child development that was seen with NaV and with CBZ.

Antiepileptic drug exposure and major congenital malformations: the role of pregnancy registries.

The use of antiepileptic drugs (AEDs) in pregnancy is associated with an increased risk of fetal malformations. Although it is known that AEDs may differ with respect to the type of malformations they can induce, earlier studies have generally lacked the power to demonstrate differences between AEDs in their overall teratogenic potential. Furthermore, there is an urgent need to assess the clinical teratogenic potential of the newer-generation AEDs. Epilepsy and pregnancy registries have been established to provide such information, which is essential for the rational management of women with epilepsy with childbearing potential. The registries also provide opportunities for additional studies of seizures observed during pregnancy and labor and, with the enrolled woman's consent, for separate studies on cognitive outcomes and pharmacogenetics. Although most are prospective, the existing registries vary somewhat in design, which needs to be considered when their results are compared. Some registries are driven by pharmaceutical companies (often compelled by national or international drug licensing agencies) and provide data on pregnancy outcome related to the sponsor's own product. Others are organized by independent research groups and are potentially more useful in that they publish comparative data. This review provides a critical discussion and comparison of important methodological aspects of AED and pregnancy registries along with a summary of results published so far.

Safety of antiepileptic drugs during pregnancy.

Women with epilepsy taking antiepileptic drugs during pregnancy have been shown to have an increased risk of having a child with a major malformation. There is some recent evidence to suggest that these drugs may also affect cognitive and behavioural development. Epilepsy is a common neurological condition and women with epilepsy constitute a significant number of pregnancies in the UK each year. Some of the drugs used to treat epilepsy are increasingly being used in the treatment of migraine and other pain syndromes and also in psychiatry principally for the control of bipolar affective disorder. This article looks at the evidence currently available in assessing the safety of the individual agents used in pregnancy.